A. The Problem
Deep venous thrombosis with the attendant risk of pulmonary embolism and post phlebitic syndrome is a frequent complication in older patients who have undergone surgery, suffered trauma or who have serious illness such as malignancy or sepsis. In any category, patients who are 40 years of age or older are considered to be at greatest risk. Also, the longer the period of immobilization, the greater the risk of DVT. Other factors that have been reported to contribute to development of DVT are obesity, prior history of DVT and smoking. While none of these factors alone or in combination will identify individual patients who will develop DVT, the incidence of DVT during the postoperative or post-traumatic period does correlate with the condition.
DVT has three major risks for the patient, two acute and one delayed. The acute problems are leg swelling, pain and tenderness, and the risk of pulmonary embolism. In pulmonary embolism part of the thrombus breaks away and is carried to the lung where it can block a pulmonary artery causing respiratory distress in proportion to the amount of blockage, i.e., to the size of the embolus. Large emboli that block both pulmonary arteries cause immediate death. The delayed problem is the post phlebitic syndrome in which there is lower extremity pain or cramps at rest, leg edema, skin changes and skin breakdown causing chronic ulcers of the lower extremity. Clinicians have long known that the post phlebitic syndrome develops in a large percentage of patients who have DVT, especially those having extensive thrombus formation. Objective studies have shown that 1-10 years following the occurrence of DVT as much as 80% of patients will have both symptoms and abnormal venous hemodynamics. While the post phlebitic syndrome is less dramatic than a major pulmonary embolus, it is a serious condition for the patients, resulting in much discomfort and expense.
In some patient groups, DVT and pulmonary embolism are major causes of morbidity and mortality. Thromboembolism is a major cause of morbidity and mortality in patients with spinal cord injury. The prevalence of DVT has been reported to range from 47% to 78%. Of these, 1 to 2% will die of pulmonary embolism. Thrombosis usually occurs 1 to 3 weeks after injury, with a peak between days 7 and 9. The incidence of thromboembolic complications in patients undergoing surgery for fractured hip is high, ranging from about 40-60%. In patients undergoing knee arthroplasty the incidence of DVT ranges from about 50% to 85%. In gynecologic malignancy the incidence of DVT was 35%. The incidence of DVT in patients undergoing elective general abdominal surgery was about 9% in those without malignancy and about 11% in those with malignancies.
An understanding of the structure and possible mechanisms of formation of venous thrombi is of direct relevance to the design of methods aimed at preventing their formation or the propagation of thrombi that have formed already.
B. Initiation and Propagation of DVT
Deep vein thrombi vary from a few millimeters in length to long tubular masses that partially or completely fill the deep main veins of the leg. These thrombi start as small nidi and initially grow in size by deposition of successive red and white layers. The white layers are rich in platelets and neutrophils interspersed with fibrin while the red layers contain mostly erythrocytes entrapped in fibrin. Beyond a certain stage of growth venous thrombi become mostly red, resembling clotted blood, i.e. the bulk of a clinically significant thrombus is composed mostly of erythrocytes entrapped in fibrin. Steps and possible mechanisms of initiation and propagation of venous thrombi are as follows:
Step 1. Thrombi are initiated at venous confluences, saccules and valve pockets throughout deep veins of the leg, thigh and pelvis. This suggests that these locations are susceptible to predisposing factor(s). It is possible, even probable, that the structure of veins at these sites is a contributing factor. Veins that have saccules, such as soleal veins in humans are reported to be thin walled and dilated. Jugular veins from dogs that had received an intravenous infusion of the vasodilators bradykinin, histamine or serotonin showed leukocyte infiltrated tears just above valve leaflets. Moreover, in the area of venous confluences the vein wall is dramatically attenuated. This could make these areas susceptible to small tears such as those found at venous confluences in canine veins. Intraoperative venous dilation was observed noninvasively by ultrasound in both animal models and patients undergoing total hip replacement. In animals, dilation correlated with the incidence of damaged confluences and in patients with subsequent development of DVT. Administration of dihydroergotamine plus low dose heparin during the pre- and postoperative period reduced venous dilation and the incidence of post operative DVT. Since these endothelial tears served as sites for accumulation of leukocytes and platelets in animals, they might serve as sites for initiation of thrombosis in humans.
Step 2. Adherent neutrophils and platelets are activated. Separately and in combination they generate/release substances that activate and attract more neutrophils and platelets. The classical example is the release of ADP by platelets. More recently it was discovered that a combination of activated neutrophils and platelets generate neutrophil activating peptide-2 (NAP-2). Cathepsin G (secreted from the granules of activated neutrophils) is capable of converting beta thromboglobulin (BTG) (secreted from alpha granules of platelets) into NAP-2 by proteolytic cleavage of 12 N-terminal amino acids from BTG. NAP-2 so generated could induce secretion of more cathepsin G which would in turn stimulate more platelet secretion, providing more substrate for generation of more NAP-2. This would constitute a positive feedback loop for accumulation of both neutrophils and platelets.
Step 3. Coagulation is initiated and promoted by the mass of activated platelets in the white layer. Activated platelets accelerate coagulation thousands of times by providing a surface for assembly of coagulation protein complexes that are necessary for conversion of prothrombin to thrombin. Activated platelets promote the catalysis of two sequential reactions in the blood coagulation cascade: the activation of Factor X to Factor Xa by a complex of Factors IXa and VIIIa and calcium ions, and conversion of prothrombin to thrombin by a complex of Factors Xa and Va and calcium ions. Platelets possess specific, high-affinity, saturable receptors for Factors Xa, V(Va), VIII, IX and IXa. Platelets are able to amplify minute stimuli to promote the local explosive formation of fibrin. This could lead to the formation of a layer of clot rich in red cells until coagulation was stopped by some as yet undefined mechanism(s). Perhaps the layer of mostly red cells entrapped in fibrin becomes sufficiently thick to physically block further dissemination of thrombin from the activated platelets or perhaps coagulation factors are inhibited.
Step 4. A new layer of neutrophils and platelets are deposited. One mechanism by which this might be initiated is by the binding of neutrophils and platelets to polymerizing fibrin. One might envision that the red layer is formed by rapid coagulation of whole blood so that leukocytes and platelets do not have time to accumulate selectively. As the red layer thickens and coagulation slows down, fibrin protofibrils are exposed at the surface of the red layer long enough to allow leukocytes and platelets to bind and accumulate selectively. Erythrocytes do not bind to polymerizing fibrin as do neutrophils and platelets. As in initiation of thrombi, generation/secretion of active substances would promote accumulation of more cells, ultimately resulting in another cycle of coagulation,
Step 5. After the nidus grows to some critical point, coagulation with entrapment of erythrocytes predominates and forms the mass of the thrombus. It has long been proposed that reduced blood flow in the immobilized patient contributes to initiation and propagation of thrombosis by allowing activated clotting factors to accumulate in the slow moving blood in the deep veins of the legs.
C. Prior Art Clinical Approaches for Prevention of Deep Venous Thrombosis
1. Overview of Prevention of DVT
From the foregoing discussion it is obvious that three characteristics dominate the initiation and propagation of venous thrombosis. First, initiation and propagation are localized to the deep veins of the legs. Second, both initiation and propagation depend on processes that are necessary for defense of the body against trauma and infection. Platelet activation (and accumulation) and blood coagulation are necessary to stop the loss of blood from disrupted blood vessels. Neutrophil response to stimulation is essential for defense of the body against infection. Third, development and propagation of thrombi are complex, involving blood clotting (thrombin generation and action), cellular interactions (platelet-platelet, neutrophil-neutrophil and platelet-neutrophil interactions) and interactions between parts of the clotting mechanisms and cellular interactions.
Initiation and propagation of DVT might be considered to represent an undesirably large response of normal defense mechanisms in the deep veins of the leg. Approaches to preventing DVT must be based on a realization that neither of these processes can be completely inhibited throughout the body for more than a brief time without serious risk of bleeding or infection.
2. Anticoagulants for Prevention of DVT
For about 50 years, efforts to prevent development of DVT and to treat those that do develop have focused on the judicious use of anticoagulants, first through full doses of oral anticoagulants and more recently through low dose heparin prophylaxis. The aim has been to achieve a helpful degree of anticoagulation (prolongation of the clotting process) without causing hemorrhage. Low dose heparin has become the standard of comparison for other preventive methods since it is relatively safe and simple and prevents approximately 65% of subclinical thrombi found by leg scanning after elective general surgery. Postoperative death from pulmonary emboli may be reduced by 65% also.
However, there are clinical situations in which low dose heparin is less effective, most notable after orthopedic surgery where the use of more complex regimens, including adjusted dose heparin and various schedules of warfarin prophylaxis are appropriate. Several studies have shown that higher levels of anticoagulation are more effective than lower ones. However, if anticoagulation is too high, bleeding complications result.
Clinical experience with the use of heparin as an anticoagulant is summarized below. In all cases, standard (unfractionated heparin) or low molecular weight heparin fragments were given subcutaneously once, twice or three times daily. No clotting parameters were measured. DVT was diagnosed by leg scan and in some cases venography.
The results of 24 studies between 1972 and 1979 were summarized by Salzman and Hirsh (1982). A total of 3,899 patients in 15 studies who underwent elective general surgery of moderate severity were given 5000 units of unfractionated heparin subcutaneously every 8 or 12 hours. The incidence of DVT ranged from 5% to 44% in untreated patients and from 1% to 13% in treated patients. In nine studies of 574 patients who underwent elective hip surgery, the incidence of DVT in untreated patients ranged from 37% to 59% and in treated patients from 7% to 46%. In a more recent study of 517 patients undergoing 638 total knee replacements, 49 patients inadvertently did not receive prophylaxis and in 41 (84%) of them ipsilateral deep vein thrombosis developed. The incidence of ipsilateral thrombosis was 57% in the 468 knee replacement patients who did receive prophylaxis. Pulmonary embolism was diagnosed clinically in 1.7% of patients but was suggested in 7% by lung scans.
Low molecular weight heparins, (LMWH), i.e. fragments derived from standard heparin, has received extensive testing in recent years. Patients undergoing general surgery were randomized to either LMWH or placebo. In a study of 4,498 general surgery patients randomized to either LMWH or placebo, there was a statistically significant difference in overall mortality between the groups, 0.8% in placebo and 0.36% in LMWH patients (P<0.05). There was also a significant reduction in thromboembolic mortality, from 0.36% in placebo group to 0.09% in LMWH group. However, there was an increase in postoperative wound hematomas and transfusion requirements in the LMWH group compared to the placebo group. No difference was detected in major bleeding. Ockelford et at (1989) randomized 183 patients to either LMWH or placebo and found that DVT was reduced from 15.9% in the placebo group to 4.2% in the treatment group.
In seven studies in which standard heparin was compared with LMWH in general surgery patients the two types of heparin had the same efficacy in general. In one study bleeding was found to be greater with LMWH while in another it was found to be less. In the other studies there was no apparent difference in bleeding.
In total hip and total knee replacement patients, in whom low dose heparin treatment leaves a high incidence of DVT (around 25%), LMWHs have been tried in three trials in which they were compared with placebo. The incidence of DVT in patients receiving LMWHs was significantly reduced in all three studies. Turpie (1991) found that a fixed dose of low molecular weight heparin (enoxaparin) reduced the rate of DVT Irma 42% to 12% in a group of patients undergoing elective total hip replacement. Proximal vein thrombi were reduced from 20% to 4%. In a group of 349 patients undergoing total hip replacement those receiving unfractionated heparin had an incidence of DVT of 16% and those receiving low molecular weight heparin had an incidence of 12.6% with the difference not being significant). In both cases the dose was adjusted and no placebo group was included.
In patients undergoing knee arthroplasty or tibial osteotomy administration of a low molecular weight heparin every 12 hours, the incidence of DVT was reduced from 65% in the placebo group to 19% in the treated group, a reduction of 71%. The incidence of proximal vein thrombi was reduced from 19% to none, a reduction of 100%. In patients undergoing elective total hip replacement, a LMWH reduced the incidence of DVT from 56.6% to 15.5%, a reduction of 74%.
In a large study (665 patients) fixed doses of unfractionated heparin and low molecular weight heparin were compared for their ability to prevent DVT in patients undergoing elective total hip replacement. In patients receiving unfractionated heparin the incidence of DVT was 232% and in those receiving low molecular weight heparin it was 19.4%. Rates of proximal vein thrombi were detected in 6.5% and 5.4% respectively. The differences were not significant.
At least five different preparations are licensed for clinical use in Europe. Large multicenter trials have been completed in Canada and the United States with promising results. Based on these studies it is probable that low molecular weight heparins will be approved for routine clinical use in North America in the near future.
Because fixed doses of heparin have failed to protect a significant percentage of orthopedic patients from DVT, more aggressive anticoagulation has been tried. The value of increasing the level of heparin anticoagulation in preventing DVT in patients undergoing elective total hip replacement was determined by Leyvraz et al (1983). In a group of 41 patients who received a fixed dose of 3500 U every eight hours 39% developed DVT. In the group of 38 patients who received adjusted dose heparin (APTT 31.5-36 seconds) only 13% developed DVT. No differences in bleeding were found. The efficacy of adjusted versus fixed low dose heparin in prevention of DVT was studied in 100 patients who had hip surgery for hip replacement or fractured neck of femur. Patients were randomized to the two groups. Significant improvement in protection against postoperative DVT was observed in the adjusted heparin group (replacement and fracture patients) (p=0.017).
Other anticoagulants have also been used in patients undergoing orthopedic surgery. Warfarin used as an anticoagulant resulted in a total incidence of DVT of 31% with an incidence of 3% proximal vein thrombosis in patients undergoing total hip replacement. No placebo group was used but these patients usually have an incidence of DVT of around 40% to 60%. Bailey et al (1991) found an incidence of DVT of 26.6% in hip replacement patients receiving low dose warfarin. Coumadin used as anticoagulant in a group of patients undergoing knee arthroplasty resulted in an overall incidence of DVT of 33% with an incidence of thigh vein thrombi of 6%. No placebo group was included but the incidence of thigh vein thrombi of 6%. No placebo group was included but the incidence of DVT in these patients is usually over 50%, sometimes being as high as 85%. The premise has now been established that less than standard doses of warfarin are efficacious. However, the dose of warfarin required to be effective without . causing bleeding complications remains to be determined in relevant clinical settings.
The rate of DVT after total knee replacement without prophylaxis has been reported to be as high as 84%. Coumadin anticoagulation and pneumatic calf compression boots have been used in an effort to reduce this rate. In 48 patients receiving coumadine the incidence of DVT was 33% with 29% having calf thrombi and 6% having thigh thrombi. In the boot group (81 patients) the total incidence of DVT was 31% with 27% having calf thrombi and 6% having thigh thrombi. No treatment related complications were reported in either group. Cost analysis showed coumadine to be approximately 50% more expensive than boots.
Patients with spinal cord injury suffer a high incidence of thrombotic complications. Green (1991) randomized 29 patients to receive a fixed dose of 5000 U of heparin subcutaneously every 12 hours compared with an equal number of patients treated with doses of heparin adjusted to prolong the APTT to 1.5 times control values; the mean dose was 13,200 U every 12 hours. Thromboembolism occurred in 31% of those on fixed dose and only 7% of those on the adjusted dose (<0.05). However, 24% of those receiving the higher dose of heparin had bleeding compared to none in the fixed group (p<0.02).
Taken together these studies demonstrates the dilemma that must be faced in administering sufficient heparin to prevent DVT without causing bleeding. They also show that the effectiveness of anticoagulation in preventing DVT does indeed depend on the dose, as would be expected.
3. Inhibitors of Platelet Function Prevention of DVT
Inhibition of platelet activation by aspirin has been tried as a method of preventing DVT. While aspirin is still given to post surgical patients, it is generally recognized that it is not effective. In a double blind randomized trial of patients having surgery after hip fracture the incidence of DVT was 46% in the placebo groups and 42% in the aspirin treated group.
4. Intermittent Pneumatic Leg Compression for Prevention of DVT
Based on repeated observations that the incidence of DVT increased with the length of time the patient was immobilized, it has been accepted that reduced blood flow (“stasis”) contributes to the thrombotic process. Therefore, means have been sought to increase blood flow in the legs of immobilized patients. These have included elastic stockings, intermittent pneumatic leg (calf and thigh) compression, passive foot motion and electrical stimulation of the calf muscle.
Intermittent pneumatic leg (calf and thigh) compression was used for preventing DVT after total hip replacement in 311 patients undergoing total hip replacement. DVT was present in 49% of controls and 24% of treated patients, with proximal vein thrombi present in 27% of controls and 14% of treated patients. Bailey et al (1991) found DVT in 6.0% of patients who were treated with sequential compression devices. Gerhart et al (1991) found DVT in 21% of patients who had operatively treated fracture of the hip. In patients undergoing total knee replacement an incidence of DVT of 33% and 19% was found.
Patients who received pneumatic sequential compression of the legs following total hip replacement had an incidence of DVT of 22% and 25%. In patients undergoing total knee replacement the incidence of DVT was 32%. This method, “pressure boots”, is used in combination with low dose heparin in two hospitals familiar to the applicants.
Prevention of DVT in patients undergoing major orthopedic surgery is cost effective. Examination by techniques of decision analysis showed the cost-effectiveness of several methods of preventing DVT. The methods included warfarin sodium, low dose subcutaneous heparin, graduated compression stockings, intermittent pneumatic compression, heparin plus dihydroergotamine meaylate, and heparin plus stockings. In untreated patients the death rate was 153 per 10,000 patients. With most prophylaxis, this number was at least halved and the most effective methods may reduce the number of deaths by three fourths. In addition, all of the prophylaxis considered were cost saving: average costs of care being reduced by +19.40 to +181.6 per patient. Throm. Res. 51 (4):447-52, 1988 and JAMA 257(2):203-8, 1987.
5. New Drugs for Prevention of DVT
Standard unfractionated heparin is currently the only agent widely used to prevent and treat DVT in the United States. However, low molecular weight heparin is used extensively in Europe and Scandinavia (see material presented in prevention and treatment). It is expected that low molecular weight heparin will soon be approved by the FDA for use in the US. Investigation of dermatan sulfate, which as heparin, is a highly sulfated mucopolysaccharide that inhibits blood clotting is not so far advanced.
Another class of possible thrombin inhibitors was suggested by recent studies on the thrombin receptor that is found on cells that are activated by thrombin. Of relevance to the pathogenesis of DVT, thrombin receptors are found on platelets and endothelium. The thrombin receptor has a thrombin cleavage site that accounts for receptor activation. The receptor also has an acidic region with some similarities to the carboxy-terminal region of the leech thrombin inhibitor, hirudin. Synthetic peptides corresponding to the receptor cleavage site (residues 38-45), the hirudin-like domain (residues 52-69) and the covalently associated domains (residues 38-64) were evaluated for their ability to bind thrombin. Peptides 38-45 and 38-64 were competitive inhibitors of the chromogenic substrate activity of thrombin.
The boroarginine peptides are also effective inhibitors of thrombin. Coagulation of plasma (activated partial thromboplastin time) was prolonged at very low (nanamolar) concentrations in vitro. Intravenous administration of boroarginine peptides to rabbits (0.2-2 mg/kg) intravenously or subcutaneously also prolonged the clotting time of plasma prepared from blood removed after the peptide was administered. One boroarginine peptide, Ac(D)-Phe-Pro-bro-Arg effectively inhibited fibrin accretion on an experimental thrombus in the rabbit jugular vein with little systemic anticoagulation. The same peptide (DuP 714) reduced the incidence of thrombosis in a rabbit model of stasis induced thrombosis from 100% to 33%. Kettner et al (1990) suggested that this new class of synthetic thrombin inhibitors may well be clinically useful as antithrombotic agents.
Another group of agents with antithrombin activity are hirudin and its derivatives. Hirudin is a natural thrombin inhibitor derived in small quantity from the saliva of Hirudinaria manillensis leeches. Use of recombinant DNA technology has enabled production of large quantities of the protein and development of a number of analogues. These have been used in 161 studies recorded in Library of Medicine as of Jan. 3, 1994. Most of these studies have been on production and characterization of recombinant proteins with a number of studies on their effects in animal models. However, three studies on humans appeared during 1993. One study (Fox et al, 1993) was on a group of human volunteers to determine the overall effects and the effect on blood coagulation and bleeding time and to study the pharmacokinetics behavior of Hirulog (BG8967). A group of 45 patients who were undergoing cardiac catheterization were randomized to receive either heparin or a hirulog as a bolus injection. Hirulog, a direct thrombin inhibitor provided a predictable level of anticoagulation without major hemorrhagic or allergic complications. In another study 291 patients pretreated with aspirin and undergoing elective coronary angioplasty were studied (Topol et al, 1993). Hirulog instead of heparin was administered to five groups in order to study the dose dependent effects of the drug. In each group the patient received the specified bolus of hirulog followed by a 4-hour intravenous infusion. The end point was abrupt vessel closure within 24 hours of initiation of the procedure. Patients in the groups receiving a higher dose of hirulog had fewer closures than those receiving lower doses, thus there was a dose dependent effect. There was only one bleeding complication and no report of adverse physiological or allergic responses. The inventors found no mention of the use of hirulogs for prevention or treatment of DVT but propose that this is a logical extension of these clinical studies.
As mentioned above, the nidus of a thrombus contains layers or zones formed of aggregates of neutrophils and platelets. Without the aggregation of neutrophils and platelets as well as the sticking of the two cell types to each other, the process of thrombus formation would not occur. Recent rapid progress in understanding the mechanisms of the interactions of these two cell types with themselves and with each other suggests new approaches for preventing DVT. One likely approach is the development of drugs that interfere with the action of “selectins” a group of receptors that are found on endothelium (E- and P-selectin), leukocytes including neutrophils L-selectin) and platelets (P-selectin).
The selectins are single polypeptide chains with external domains composed of three types of smaller domains that resemble other proteins. The N-terminal end of the peptide is a calcium requiring lectin-like domain. This is followed by an epidermal growth factor domain and variable numbers of complement regulatory protein-like repeating units. All three selectins are heavily glycosylated. This property is proving to be of great significance in their function.
In all three families, some receptors are present on the cell surface constitutively while in other cases stimulation of the cell is required for surface exposure or activation of the receptor. There are two means for stimulating exposure of receptors. In one case stimulation causes the exposure of preexisting receptors within seconds or minutes while in other cases receptors must be synthesized de novo, a process requiring a few hours. In still other cases activation of the cell apparently causes a change in conformation of existing, inactive receptors so that thcy become active.
L-Selectin is constitutively expressed on PMN and participates in PMN-EC recognition/adhesion. Monoclonal antibodies to L-selectin inhibit PMN localiiation at sites of acute inflammation in vivo and block PMN binding to cytokine-activated EC in vitro. L-selectin appears to be a major ligand (or receptor) involved in leukocyte rolling along veins in thin membranes. This is the earliest event in leukocyte adhesion observed in many studies of ethin membranes over the years. In a rabbit model monoclonal antibodies against L-selectin inhibited up to 80% of intravascular leukocyte “rolling”. Interestingly, L-selectin interacts with E-selecting and P-selectin to produce PMN binding to EC. L-selectin is shed, probably by proteolytic cleavage, from both PMN and lymphocytes after cellular activation). This down regulation of L-selectin suggests that it might be necessary to inhibit neutrophil adhesion for a relatively short time during and after an operation to prevent their binding to the vein.
Platelets, as EC have P-seleetin in their granules. This can be translocated to the surface during stimulated secretion and is responsible for adhesion of stimulated platelets to PMN. This is most likely of major importance in the early development of thrombi since platelet/neutrophil masses form the nidus of thrombi.
Small carbohydrates modeled on the structure of the carbohydrate residue that confers activity and specificity on a group of receptors (selectins) found on platelets, neutrophils and endothelium are being used in experimental inflammation and metastasis and may be applicable for use in preventing or treating DVT. Administration of all of these inhibitors by a route that increased their concentrations in the blood of deep leg veins would increase their inhibitory activity locally while minimizing undesirable effects systemically.
Despite the progress that has been made in reducing the incidence of DVT, a sizable percentage of patients undergoing major orthopedic and gynecological operations as well as those sustaining spinal cord injury still develop thromboembolic complications including DVT, pulmonary embolism and the postphlebitic syndrome. Moreover, there are some patient groups in whom low dose heparin has not been successful. These include intracerebral hemorrhage in which low dose heparin was ineffective. Patients undergoing radical prostatectomy had an incidence of 11% pulmonary emboli. This was reduced to none in patients receiving mini-dose heparin but bleeding complications in the treated group were unacceptably high. These observations clearly indicate that better prophylaxis is needed.
D. Treatment of Existing DVT
The classical treatment of DVT is the use of intravenous heparin. Adjusted dose intravenous heparin given by continuous infusion for the initial treatment of patients with proximal vein thrombosis resulted in an incidence of 6.9% of new episodes of venous thromboembolism. Major bleeding associated with initial therapy occurred in 5% of these patients. No placebo group was possible.
The efficacy and safety of adjusted subcutaneous heparin was compared with continuous intravenous heparin as the initial treatment for acute deep vein thrombosis. In both groups heparin was adjusted to maintain the activated partial thromboplastin time between 50-70 seconds. There was no significant difference between the two groups in the rate of new pulmonary embolism. Five of 47 in the subcutaneous group and 5 of 49 in the intravenous grouped developed pulmonary embolism (10.6% and 10.2% respectively). Similarly there was no difference in the rate of hemorrhagic complications (9.8%).
Unfractionated heparin was administered subcutaneously in doses adjusted according to the activated partial thromboplastin time (1.5-2 times pretreatment values). There was improvement in {(fraction ( 32/66)} 48% of patients but an increase in thrombus size in 12/66 18%. One symptomatic non-fatal pulmonary embolism and one major bleeding episode occurred. In a similar study Prandoni et al (1992) found that 14% of 85 patients suffered recurrent venous thromboembolism diagnosed objectively. A similar study found that adjusted dose intravenous standard heparin improved the mean Marder score in 61% of 49 patients.
These studies show that treatment of existing DVT with heparin administered intravenously or subcutaneously are ineffective in upwards of 50% of patients and that many patients develop hemorrhagic complications.